Complexes of 2-substituted benzimidazoles and bis-halogenated phenols



Preferred among the foregoing are:

2- (4'-thiazolyl -b enzimidazole 2,2'-thi0bis (4,6-dichlorophenol) 2- (4'-thiazolyl benzimidazole 2,2'-sulfinylbis (4,6-dichlorophenol 2- (4-thiazolyl benzimidazole 2,2'-sulfinylbis (3-methyl-4,6-dichlorophenol) 2- (4'-thiazolyl benzimidazole 2,2'-thiobis (3,4,6-trichlorophenol 2- 4'-thiazolyl benzimidazole 2,2'-thiobis (3-methyl-4,6-dichlorophenol 2- (4-thiazolyl benzimidazole 2,2-sulfinylbi (3,4,6-trichlorophenol 2- (4'-thiazolyl benzimidazole 2,2'-thiobis (4-chloro-6-nitrophenol) 2-( 2.-thiazolyl benzimidazole 2,2'-thiobis (4,6-dichlorophenol 2- (2'-thiazolyl benzimidazole 2,2-thiobis (3 ,4,6-trichlorophenol 2- 2'-thiazolyl benzimidazole 2,2'-sulfinylbis (3 ,4,6-trichlorophenol 2-(2-thiazo1yl) benzimidazole 2,2'-thiobis (4-chloro-6-nitrophenol) Z-phenyl benzimidazole 2,2'-thiobis (4,6-chlorophenol 2-phenyl benzimidazole-2,2'-thiobis v (3 ,4,6-trichlorophenol) 2-phenyl benzimidazole 2,2'-sulfinylbis (4,6-dichlr0phenol 2-phenyl benzimidazole 2,2'-sulfinylbis (3,4,6-trichlorophenol) Z-phenyl benzimidazole 2,2-thiobis (4-chloro-6-nitrophenol) 2- 2'-pyrryl benzimidazole 2,2'-thiobis (4,6-dichlorophenol 2- 2-pyrryl) benzirnidazole 2,2'-thiobis (3,4,6-trichlorophenol 2-(2-furyl benzimidazole 2,2'-thiobis (4,6-dichlorophenol) 2-( 2-furyl benzimidazole 2,2-thiobis (3 ,4,6-trichlorophenol) 2- (2'-thienyl benzimidazole 2,2'-thiobis (4,6-dichlorophenol 2- 3-thienyl benzimidazole 2,2-thiobis (4,6-dichlorophenol), and

2- 4'-thiazolyl -5-methyl benzimidazole 2,2'-thiobis (4,6dichlorophenol and most preferred are:

2- (4'-thiazolyl) -benzimidaz0le 2,2'-thiobis (4,6-dichlorophenol) 2- 4'-thiazolyl) benzimidazole 2,2-sulfinylbis (4,6

dichlorophenol) 2- (4-thiazolyl benzimidazole 2,2'-thiobis 3,4,6-

trichloro phenol) 2- 4-thiazolyl) benzimidazole 2,2'-sulfinylbis( 3,4,6-

trichlorophenol) 2- (4-thiazolyl benzimidazole 2,2'-sulfinylbis 3-methyl- 4,6-dichlorophenol 2-(4-thiazolyl -benzimidazole 2,2'-thiobis 3 -methyl-4,6

dichlorophenol) 2- (2-thiazolyl benzimidazole 2,2-thiobis (4,6-dichlorophenol),

2-( 2'-thiazolyl benzimid azole 2,2-thiobis 3,4,6-trichlorophenol) 2-phenyl benzimidazole 2,2'-thiobis(4,6-dichlorophenol),

2-phenyl benzimidazole 2,2-thiobis 3,4,6-trichlorophenol) 2-( 2'-pyrryl) benzimidazole 2,2'-thiobis (4,6-dichlorophenol),

2- 2-pyrryl benzimidazole 2,2'-thiobis( 3,4,6-trichlorophenol 2-( 2'-furyl benzimidazgle 2,2 -thiobi s(4,6-dichlorophenol),

4 2-(2'-furyl)benzimidazole 2,2'-thiobis 3,4,6-trichlorophenol), and 2- 3 '-thienyl benzimidazole 2,2-thiobis (4,6-dichlorophenol).

The novel compounds of the invention are prepared by reacting a benzimidazole of theformula:

l. with a bis-halogenated phenol of the formula:

R4- R5 R4 Where R, R R R R R and R are as previously assigned. In general, the reaction may be effected by mixing the reactants in a suitable solvent, and heating the mixture if necessary to effect solution. Solvents such as methanol, ethanol, propanol, butanol, acetone, and the like may be employed with methanol being preferred. The product can be recovered by cooling the reaction mass to a point where the product crystallizes from solution.

It is preferred to use an excess of the bisphenol compound in the reaction medium over the stoichiometric amount since these are generally more soluble than the benzimidazole compounds. Such excesses of bisphenol compound, however, are not critical and equimolar amounts or excesses of the benzimidazole reactant may be used if desired.

The temperature of the reaction is not critical. The particular temperature employed will depend to a large extent on the reactants employed and on the solvents used. The preferred reactant temperature is the reflux temperature of the solvent system employed. Once solution has been effected, as indicated by clarification of the reaction mass, the product, the complex between the benzimidazole compound and the bis-halogenated compound, may be crystallized from solution by cooling the reaction mass, preferably to a temperature somewhat below room temperature. Values in the range of from 0-15 C. are suitable for this purpose. The product may then be washed and dried in accordance with known techniques.

The compounds of the present invention have utility in the field of animal therapy. They are highly effective anthelmintics and are effective against a wide spectrum of helminths. For example, they are effective against roundworm, tapeworm and fiukes in such animals as sheep, cattle, goats, horses, and mules, the actual degree of anthelmintic activity depending upon the particular complex. For effective treatment certain dosage levels are desired, depending upon the complex employed, the type of animal, and the particular helminth being combatted. For the complexes:

2-(4'-thiazolyl) benzimidazole 2,2'-thiobis (4,6-dichlorophenol),

2- (4'-thiazolyl)benzimidazole 2,2'-thiobis(3,4,6-trichlorophenol),

2-(4'-thiazolyl) bcnzimidazole 2,2-sulfinylbis (4,6-dichlorophenol) 2-(4-thiazolyl) benzimidazole -2,2'-sulfinylbis(3,4,6-trichlorophenol) 2-(2-thiazolyl)benzimidazole 2,2'-t;hiobis (4,6-dichlorophenol),

2-( 2-thiazoly1)benzimidazole 2,2'-thiobis( 3,4,6-trichlorophenol) 2-(2-pyrryl) benzimidazole 2,2-thiobis (4,6-dichlorophenol),

2- 2-pyrryl benzimidazole 2,2-thiobis (3 ,4,6-trichloro- 2- (2.-furyl )benzimida'zole 2,2"-thiobis 4,6-dichlorophenol),

2- (2'-furyl) benzimidazole 2,2'-thiobis 3,4,6-trichlorophenol), and 1 I I 2- (3 -thienyl)benzimidazole 2,2-thiobis (4,6-dichloro- A phenol),

eflective roundworm, tapeworm and fluke efficacy is achieved when the complex is administered at dosage levels of from 65 to 425 mg./kg. For the complexes 2- phenyl benzimidazole-2,2 thiobis(4,6 dichlorophenol) and 2 phenyl benzimidazole-2,2 thiobis(3,4,6 trichlorophenol), good tapeworm and fluke eflicacy is obtained at the above dosage level.

The compounds of the present invention may be administered in a variety of ways, depending upon the particular animal employed, the type of anthelmintic treatment normally given to such an animal, the materials employed, and the particular hehninths being combatted. Irrespective of the method of treatment, the complexes of the present invention may be admixed with any inert carrier and administered to the animal. A convenient range of active ingredients in the composition is from 0.001%-95% by weight, based on the total weight of the composition. The actual amount of complex included will, as above stated, depend upon the particular mode of treatment. Thus, where the treatment involves admixing the active ingredient with an animals feed, and is prophylactic, the amount of material may suitably range between 0.001%3.0% by weight with the carrier being an element of the animals nutrition. Where the feeding method is employed therapeutically, the composition may contain from 0.05-25% of the complex, based on the total weight of the feed.

When the method of treatment involves using unit dosage forms such as tablets, boluses or a liquid drench, the active ingredient may suitably range from about 5-95% based on the total weight of the composition with a range of from 580% being suitable for the solid dosage forms, a range of from 30-95% of dry dispersible powder suitable for forming the liquid drench, and a range of from -50 for the final liquid drench form.

Additionally, the complexes of the present invention may be admixed with orally ingestible carriers for subsequent admixing into the animals feed. These are normally termed feed pre-mixes or supplements and they conveniently contain from about 550% by weight of the complex material.

The following examples are given for purposes of illustration only and are not intended to limit the scope of the present invention. EXAMPLE 1 2 g. of 2-(4'-thiazolyl)benzimidazole and 4 g. of 2,2- thiobis(4,6-dichlorophenol) are mixed in 100 cc. of methanol. The reaction mixture is brought to a reflux temper ature of about 64 C. and is held there until the solution is complete, a period of about 5 minutes. The reaction mass is then cooled overnight at a temperature of 4 C. The product, 2 (4'-thiazolyl)benzimidazole-2,2'-thiobis (4,6-dichlorophenol) crystallizes in the form of slightly colored crystals. It is then filtered and dried at 50 C. in an oven drier.

When equivalent amounts of 2-(2-thiazolyl)benzimidazole, 2-phenyl benzimidazole, 2-(2-pyrryl)b enzimidazole, 2-(2-furyl)benzimidazole, 2-(3-thienyl)benzimidazole, 1-methyl-2-(4-thiazolyl)benzimidaiole, 2-(4'-thiazolyl)-5-methyl benzimidazole, 2-(4'-thiazo1yl)-5-trifluoromethyl benzimidazole and 2-(3'-thienyl)-5,6-dimethoxy benzimidazole are substituted for the 2-(4thiazolyl)benzimidazole'in'the foregoing procedure, the corresponding complex is formed.

When the 2,2 thio-bis(4,6-dichlorophenol) is replaced with an equivalentamount of 2,2-thiobis(4-chloro-6- nitrophenol) in the above procedure, the corresponding complex is obtained. I

Similar results are obtained when the methanol in the foregoing procedure is replaced with ethanol, propanol, butanol, or acetone and the reaction mass is heated to the reflux temperature of the system. H 1

EXAMPLE 2 A suspension of 7.9 g. (0.0179 mole) of 2,2'-sulfinylbis (3,4,6-trichlorophenol) and 2.69 g. (0.013 mole) of 2-(4'- thiazolyl)benzimidazole in 250 ml. of methanol is refluxed overnight. Undissolved 2 (4' thiazolyl)benzimida zole (1.17 g.) is removed by filtration and the filtrate is concentrated to a residual volume of about 50 ml. via atmospheric distillation. The resulting slurry is cooled to 0 C., aged briefly, filtered, washed with a little methanol and air dried. 2.7 g. of the product, 2(4'-thiazolyl)benz.imidazole-2,2-sulfinylbis(3,4,6-trichlorophenol), M.P. 191 C., are obtained. X-ray studies and U.V. absorption characteristics indicate that the product is a discrete compound having a 1:1 molar ratio of the constituent reactants.

When the above procedure is repeated using an equivalent amount of 2,2'-sulfinylbis(3-methyl-4,6 dichlorophenol) or 2,2'-sulfinylbis(4,6-dichlorophenol) in place of the 2(2 sulfinylbis( 3,4,6 trichlorophenol), the corresponding complex is obtained.

When equivalent amounts of 2-(2'-thiazolyl)benzimidazole, 2 phenyl benzimidazole, 2-(2-pyrryl)benzimidazole, 2-(2-furyl)benzimidazole, 2-(3'-thienyl)benzimidazole, l-methyl-2(4-thiazolyl)benzimidazole, 2-(4'-thiazolyl)-S-methyl benzimidazole, 2-(4'-thiazolyl) 5 trifiuoromethyl benzimidazole and 2-(3-thienyl)-5,6-dimethoxy benzimidazole are substituted for the 2-(4-thiazolyl)benzimidazole in the foregoing procedure, the corresponding complex is formed.

EXAMPLE 3 A suspension of 42.5 g. (0.1 mole) of 2,2'-thiobis(3,4,6- trichlorophenol and 10. 0 g. (0.05 mole) of 2-(4'-thiazolyl)benzimidazole in 1.5 l. of methanol is refluxed briefly to effect solution, concentrated to about one-half initial volume, filtered to clarify and the filtrate cooled overnight at 0 C. The resulting crystalline mass is filtered, the cake washed with 2 x 50 ml. of cold methanol and then dried atmospherically. The product, 2-(4-thiazolyl) benzimidazole-2,2'-thiobis( 3,4,6 trichlorophenol), M.P. 203-204.5 C., is obtained in the form of small needles. X-ray studies and U.V. absorption characteristics indicate that the product is a discrete compound having a 1:1 molar complex of the constituent reactants.

When the above procedure is repeated using an equivalent amount of 2,2'-thiobis(3methyl-4,6-dichlorophenol) in place of the 2,2-thiobis(3,4,6-trichlorophenol), the corresponding complex is obtained.

When equivalent amounts of 2-(2'-thiazolyl)benzimidazole, 2-phenyl benzimidazole, 2-(2' -pyrryl)benzimidazole, 2-(2.-furyl)benzimidazole, 2-(3-thienyl)benzimidazole, 1-methyl-2-(4-thiazolyl)benzirnidazole, -2-(4-thiazolyl) 5 methyl benzimidazole, 2-(4'-thiazolyl)-5-trifiuoromethyl benzimidazole and 2-(3'-thienyl)-5,6-dimethoxy benzimidazole are substituted for the 2-(4'-thiazolyl)benzimidazole in the foregoing procedure, the corresponding complex is formed.

EXAMPLE 4 A total of 66 g. of the complex 2-(4'-triazolyl)benzimidazole 2,2-thiobis(4,6-dichlorophenol) obtained from Example 1 is suspended in one quart of water along with the following ingredients:

Grams Polysorbate polyoxyethylene (20) sorbitan monooleate (Tween 80; available from Atlas Chem.

Co.) 0.4 Sorbitan monolaurate (Span 20; available from Atlas Chem. Co.) 0.4 Pre-gelatinized starch 39.2

The total volume of the drench obtained after one quart of water is added in 33 fluid ounces. Two groups of two sheep each, naturally infected with nemotodes of the following genera, are selected: Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Strongyloides, Nematodirus, and Oesophagostomum. One group serves as a control group and does not receive treatment. The drench is administered in a dosage equivalent to provide 138 mg. of the complex per kg. of animal body weight. The fecal egg counts are obtained on both the untreated controls and the treated animals, before and after treatment. The following table shows the results obtained.

Fecal ggematode Egg Count P.G.), Days Pretreatment Post-treatment Dosage Sheep Medication (mg/kg.) No. 3 2 8 6 7 1 Eggs per gram feces.

1 2-(4-thiazolyl)benzimidazole-2,2-thiobis (4,6-dichlorophenol) It will be observed from the above table that within 48 hours after treatment one treated sheep had an undetectable nemotode egg count, while another sheep had an E.P.G. of only 4, whereas the untreated controls maintain a detectable egg count throughout the one-week posttreatment period.

EXAMPLE 5 Three sheep weighing 51, 41, and 45 kg. and naturally infected with the tapeworm Moniezia expansa as determined by pre-treatment fecal examination, are treated with a drench containing the complex 2-(4-thiazolyl)- benzimidazole 2,2'-thiobis (4,6-dichlorophenol) prepared from the formulation of Example 1 at a dosage level of 138 mg. of complex per kg. of body weight. At necropsy, four days after treatment, the small intestine of each sheep is examined for proglottids and scolices of Moniezia and none is found.

EXAMPLE 6 Four groups of rats are experimentally infected with the sheep liver fluke Fasciola hepatica and kept on a normal diet. The infection is allowed to proceed on a natural course for the period of time indicated in the table below. The rats are then treated with a single oral dose of the complex 2-(4-thiazolyl)benzimidazole-2,2- thiobis(3,4,6-trichlorophenol) in an aqueous suspension containing 2% methyl cellulose. The medicament is administered at a level of 50 mg./kg. of animal body weight. About 5 days after treatment the rats are necropsied and their bile ducts examined for the extent of infection. The results are summarized in the table below:

Approximate Age of infection weight of rat at treatment at treatment Therapeutic (weeks) (gm.) Response 12 450 Died. 12 450 Complete. 12 450 D0. 12 450 D0.

1 Designation given when all liver fluke present in bile duct are dead.

It will be appreciated by those skilled in the art that the infections in rats 5, 6 and 7 are immature at the time of treatment, an extremely intractable stage. The complete therapeutic response therefore in these animals is noteworthy.

8 EXAMPLE 7 A formulation containing the following ingredients is prepared and brought up to 976 ml. volume with water:

Each ounce of the above formulation contains 5.71 g. of complex. This formulation is administered in a single oral dose to each of four sheep naturally infected with nematodes including Trichostrongylus, Ostertagia, and Cooperia at the dosage level indicated in the table below. Dosages are indicated in terms of the amount of complex supplied. Fecal egg counts are made about 7 days after treatment. The results are tabulated below:

Fecal Nematode Egg Count (Eggs per gm.), Days Posttreatment Pretreatment coco As can be seen from the above table, egg counts drop to zero within 7 days after treatment, thus showing a complete therapeutic response to the medicament.

What is claimed is:

1. A compound of the formula OH on -N R4 l R5 J R4 n I ll 1 N/R Re R l l 01 Cl R1 where R is selected from the group consisting of thiazolyl, isothiazolyl, thiadiazolyl, pyrryl, furyl, thienyl and phenyl, R is selected from the group consisting of hydrogen, lower alkyl, and alkenyl, R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, and trifluoromethyl, R is selected from the group consisting of halogen and nitro, R is selected from the group consisting of S- and SO, and R is selected from the group consisting of hydrogen, chloro, and lower alkyl.

2. A compound of claim 1 wherein R is 4'-thiazolyl, and R R and R are hydrogen.

3. A compound of claim 2 wherein R is -S.

4. A compound of claim 2. wherein R is SO-.

5. The compound of claim 3 wherein R is chloro and R is hydrogen.

6. The compound of claim 4 wherein R is chloro and R is hydrogen.

7. The compound of claim 3 wherein R and R are chloro.

8. The compound of claim 4 wherein R and R are chloro.

9. A compound of claim 1 wherein R is chloro and R is hydrogen.

10 10. A compound of claim 1 wherein R and R are 3,162,574 12/1964 Forsyth. chloro. 3,025,575 8/1965 Kruyt.

References Cited UNITED STATES PATENTS HENRY R. JILES, Pnmary E xammer 5 NATALIE TROUSOF, Assistant Examiner 2,857,391 10/1958 Engelhardt et a1. 260-3092 2,891,070 6/1959 Ledrut 2-60311 3,017,415 1/ 1961 Sarett et al. 260309.2, 607, 609; 424270, 273 3,152,041 10/1964 Gillingham et a1. ..16753 

